ORCID Profile
0000-0003-4580-1840
Current Organisation
University of St Andrews
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Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.EXER.2018.03.023
Abstract: Age-related macular degeneration (AMD) is associated with the formation of sub-retinal pigment epithelial (RPE) deposits that block circulatory exchange with the retina. The factors that contribute to deposit formation are not well understood. Recently, we identified the presence of spherular hydroxyapatite (HAP) structures within sub-RPE deposits to which several AMD-associated proteins were bound. This suggested that protein binding to HAP represents a potential mechanism for the retention of proteins in the sub-RPE space. Here we performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on plasma s les from 23 patients with late-stage neovascular AMD following HAP-binding. In iduals were genotyped for the high risk CFH variant (T1277C) and binding to HAP was compared between wild type and risk variants. From a library of 242 HAP binding plasma proteins (1% false discovery rate), SWATH-MS revealed significant quantitative differences in the abundance of 32 HAP-binding proteins (p < 0.05) between the two homozygous groups. The concentrations of six proteins (FHR1, FHR3, APOC4, C4A, C4B and PZP) in the HAP eluted fractions and whole plasma were further analysed using ELISA and their presence in sections from human cadaver eyes was examined using immunofluorescence. All six proteins were found to be present in the RPE/choroid interface, and four of these (FHR1, FHR3, APOC4 and PZP) were associated with spherules in sub-RPE space. This study provides qualitative and quantitative information relating to the degree by which plasma proteins may contribute to sub-RPE deposit formation through binding to HAP spherules and how genetic differences might contribute to deposit formation.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2022
DOI: 10.1038/S43856-022-00137-0
Abstract: Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves. Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively. The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient’s genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2022
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0SC06605B
Abstract: Zn 2+ is an essential regulator of coagulation. In plasma, Zn 2+ availability is fine-tuned by human serum albumin (HSA). Here we show that elevated fatty acid levels contribute to altered coagulation in type-2 diabetes through Zn 2+ mishandling by HSA.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alan J. Stewart.